Cannabis is best known as a psychotropic drug of abuse;yet this plant has medicinal properties. Some patients with multiple sclerosis (MS) use marijuana in an attempt to relieve their symptoms and several animal studies have confirmed the analgesic properties of cannabinoid compounds. Evidence now shows that CB2 receptors are expressed in the CMS and CB2 agonists may actually be used as therapeutics. Indeed, when given to mice developing experimental autoimmune encephalomyelitis (EAE), CB2 receptor agonists prevent microglia activation, T-cell infiltration and favor remyelination. While very promising, these results require further testing and characterization. In the prior funded cycle, we discovered that microglia produce and inactivate the most abundant endocannabinoid (eCB), 2-arachidonoylglycerol (2-AG), and express CB2 receptors, which regulate their migration. Given that activated microglia determine the onset and maintenance of EAE, we propose that activation of CB2 receptors by 2-AG regulates microglial cell recruitment toward lesion sites. Because activated microglia express high levels of CB2 receptors, they represent a valuable target for the development of specific therapies designed to control neuroinflammation. We will test our hypotheses by addressing three aims. To what extent are CB2 receptors required for microglial cell migration? How do cytokines affect eCB signaling in microglia? Do CB2 agonists and antagonists control microglia cell migration in vivo and EAE pathogenesis? Completion of these aims will establish the mechanisms of action and pre-clinical efficacy for the use of compounds acting through CB2 receptors as therapy for MS. In doing so, we will also gain a better understanding of the molecular mechanism controlling eCB signaling in the CMS.